Late-Onset Unexplained Seizures Are Associated With Cognitive Impairment and Lower Amygdala Volumes

Sarkis RA, Orozco J, Lemus HN, Hankerson A, Liu L, Lam AD, Johnson E, Stufflebeam S, Viswanathan A, Amariglio RE, Purandare M, Trouten P, Young GS, Locascio JJ, Pennell PB, Marshall GA. Brain Commun. 2025 Jan 31;7(1):fcaf050. doi:10.1093/braincomms/fcaf050. PMID: 39944741; PMCID: PMC11815171.

Late-onset epilepsy has been linked with accelerated cognitive decline and a higher risk of dementia. In this study, we sought to characterize the cognitive profile of participants with late-onset unexplained epilepsy and compare their MRI findings to healthy controls, to better understand underlying disease mechanisms. We recruited participants with at least one new-onset unexplained seizure at age 55 or later, without cortical lesions on MRI, within 5 years of the first seizure. We administered a neuropsychological battery to generate Preclinical Alzheimer Cognitive Composite and composite scores for delayed verbal recall, processing speed and executive function. We held a consensus meeting to determine whether the participants fulfilled criteria for mild cognitive impairment. An MRI volumetric analysis of hippocampal, amygdalae, and white matter hyperintensity volume was performed and compared to 353 healthy controls from the Harvard Aging Brain Study. On late-onset unexplained epilepsy participants, we also obtained 24-h EEG recording. Seventy participants were recruited, mean age 71.0 ± 7.0 years, 49% female, 15.6 ± 3.0 years of education. Impaired cognition (z-score ≤ −1.5) for late-onset unexplained epilepsy included the following: 15.9% for Preclinical Alzheimer Cognitive Composite −5, 23.2% for delayed verbal recall, 15.6% for processing speed, and 7.5% for executive function. Seventeen percent were found to have mild cognitive impairment. Late-onset unexplained epilepsy participants who were drug resistant were more likely to have cognitive impairment (50% vs. 9%). When controlling for age, sex, and race, late-onset unexplained epilepsy group had lower left AV (%; β = −0.003, P = 0.0016), right AV (%) (β = −0.003, P = 0.01), and log-transformed WMV (mm³; β = −0.21, P = 0.03) compared with Harvard Aging Brain Study (HABS); there were no differences in left or right HV between groups. EEG captured epileptiform abnormalities in 49% late-onset unexplained epilepsy participants, with a left temporal predominance (54%). In this single-site study of prospectively enrolled participants with late-onset unexplained epilepsy, we show that individuals with late-onset unexplained epilepsy exhibit cognitive impairments, mostly in verbal memory, and temporal dysfunction with left-sided predominance. Neuroimaging, when compared with healthy controls, shows lower amygdalae and white matter hyperintensity but not hippocampal volumes suggesting that the amygdalae is one of the earliest sites involved in the disease. The results also highlight the importance of seizure control given the association between mild cognitive impairment and drug-resistant epilepsy. Future studies extending these findings to Alzheimer's disease biomarkers and longitudinal follow-up will inform predictors of cognitive decline.

Association of Cognitive and Structural Correlates of Brain Aging and Incident Epilepsy. The Framingham Heart Study

Stefanidou M, Himali JJ, Bernal R, Satizabal C, Devinsky O, Romero JR, Beiser AS, Seshadri S, Friedman D. Epilepsia. 2025;66(1):160–169. doi:10.1111/epi.18160. Epub Nov 18, 2024. PMID: 39555677; PMCID: PMC11875459.

Objectives: Late-onset epilepsy has the highest incidence among all age groups affected by epilepsy and often occurs in the absence of known clinical risk factors such as stroke and dementia. There is increasing evidence that brain changes contributing to epileptogenesis likely start years before disease onset, and we aim to relate cognitive and imaging correlates of subclinical brain injury to incident late-onset epilepsy in a large, community-based cohort. Methods: We studied Offspring Cohort of the Framingham Heart Study participants 45 years or older, who were free of prevalent stroke, dementia, or epilepsy, and had neuropsychological (NP) evaluation and brain magnetic resonance imaging (MRI). Cognitive measures included Visual Reproduction Delayed Recall, Logical Memory Delayed Recall, Similarities, Trail Making Test B minus A (TrTB-TrTA; attention and executive function), and a global measure of cognition derived from principal component analysis. MRI measures included total cerebral brain volume, cortical gray matter volume (CGMV), white matter hyperintensity volume (WMHV), and hippocampal volume. Incident epilepsy was identified through a review of administrative data and medical records. Cox proportional hazards regression models were used for the analyses. All analyses were adjusted for age, sex, and educational level (cognition only). Results: Among participants who underwent NP testing (n = 2349, 45.81% male), 31 incident epilepsy cases were identified during follow-up. Better performance on the TrTB-TrTA was associated with a lower risk of developing epilepsy (hazard ratio [HR] .25, 95% confidence interval [CI] .08–.73; p = .011). In the subgroup of participants with MRI (n = 2056, 46.01% male), 27 developed epilepsy. Higher WMHV was associated with higher epilepsy risk (HR 1.5, 95% CI 1.01–2.20; p = .042), but higher CGMV (HR .73, 95% CI .57–.93; p = .001) was associated with lower incidence of epilepsy. Significance: Better performance on the (TrTB-TrTA), a measure of executive function and attention, and higher cortical volumes are associated with lower risk of developing epilepsy. Conversely, higher WMHV, a measure of occult vascular injury, increases the risk. Our study shows that non-invasive tests performed in mid-life may help identify people at risk for developing epilepsy later in life.

Search results

Crossover Phenomena in Epileptic Syndromes of Childhood

Does Grey Matter? The Structural and Cognitive Footprint of Late-Onset Epilepsy